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Toxins (Basel)
2018 Aug 21;109:. doi: 10.3390/toxins10090337.
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Phoneutria nigriventer Spider Toxin PnTx2-1 (δ-Ctenitoxin-Pn1a) Is a Modulator of Sodium Channel Gating.
Peigneur S
,
Paiva ALB
,
Cordeiro MN
,
Borges MH
,
Diniz MRV
,
de Lima ME
,
Tytgat J
.
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Spider venoms are complex mixtures of biologically active components with potentially interesting applications for drug discovery or for agricultural purposes. The spider Phoneutria nigriventer is responsible for a number of envenomations with sometimes severe clinical manifestations in humans. A more efficient treatment requires a comprehensive knowledge of the venom composition and of the action mechanism of the constituting components. PnTx2-1 (also called δ-ctenitoxin-Pn1a) is a 53-amino-acid-residue peptide isolated from the venom fraction PhTx2. Although PnTx2-1 is classified as a neurotoxin, its molecular target has remained unknown. This study describes the electrophysiological characterization of PnTx2-1 as a modulator of voltage-gated sodium channels. PnTx2-1 is investigated for its activity on seven mammalian NaV-channel isoforms, one insect NaV channel and one arachnid NaV channel. Furthermore, comparison of the activity of both PnTx2-1 and PnTx2-6 on NaV1.5 channels reveals that this family of Phoneutria toxins modulates the cardiac NaV channel in a bifunctional manner, resulting in an alteration of the inactivation process and a reduction of the sodium peak current.
Figure 1. Sequence alignment of PnTx2-1 with NaV-channel toxins from Phoneutria nigriventer venom fraction 2.
Figure 2. Electrophysiological profiles of PnTx2-1 on NaVs. Panels show superimposed current traces of 1 μM PnTx2-1. The dotted line indicates zero current level. Black, current trace in control conditions; red, current trace in toxin situation. The asterisk marks steady-state current trace after application of 1 µM peptide. The last panel shows the concentration–response curves for PnTx2-1 on different NaV channel isoforms.
Figure 3. Electrophysiological characterization of PnTx2-1 on mammalian NaV channels. Left panels show the current voltage relationships and the right panels show the steady-state activation (closed symbols) and inactivation (open symbols) curves in control (black) and toxin conditions (1 µM PnTx2-1, blue) for NaV1.1 (A), NaV1.5 (B) and NaV1.8 (C). (D) Recovery from inactivation for NaV1.5 channels. Control conditions (black symbols) and in the presence of 1 µM PnTx2-1 (red symbols) are shown. (E) Competitive experiments to indicate that PnTx2-1 does not bind at site 1. Representative traces for NaV 1.5 channels are shown in control; after application of 500 nM tetrodotoxin (TTX) and after subsequent addition of 90 nM PnTx2-1.
Figure 4. Electrophysiological characterization of PnTx2-1 on insect NaV channels. (A) Steady-state activation (closed symbols) and inactivation (open symbols) curves in control (black) and toxin conditions (1 µM PnTx2-1, blue) for BgNaV1.1. (B) Recovery from inactivation in control (black symbols) and in the presence of 1 µM PnTx2-1 (red symbols). (C) Investigation of the state-dependence of indicating that an expected degree of channel inactivation inhibition was observed after the 2 min incubation, indicating that the open state is not required for toxin interaction with the channel.
Figure 5. Electrophysiological characterization of PnTx2-6 on NaV1.5. (A) Representative whole-cell current traces in control (black) and toxin (red) conditions are shown. The dotted line indicates the zero-current level. The asterisk marks steady-state current trace after application of 1 µM peptide. (B) Concentration–response curve for PnTx2-6 on NaV1.5. (C) Current–voltage relationship in control conditions and in the presence of 200 nM PnTx2-6. (D) Steady-state activation (closed symbols) and inactivation (open symbols) curves in control (black) and toxin conditions (1 µM PnTx2-6, blue) for NaV1.5 channels.
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